The Portland cohort study of 24,000 women was completed in 2001 and specimen testing has now been completed. We observe (Dr. Schiffman) that the most important types of HPV, called HPV16 and HPV18, predict much high absolute risks of cervical cancer and precancer in prospective follow-up lasting 15 years, despite screening. The Portland cohort study is now effectively finished, with the final publications due this coming year. Other, nearly completed and large prospective projects include the ALTS clinical trial and the Guanacaste cohort analyses, both in the final testing and analyses phases. Based on HPV typing of all 20,000 specimens from the 5,000 ALTS participants, we are examining the diverse natural histories of the carcinogenic and non-carcinogenic HPV types, and the influences of co-factors. This study is still useful for validating new HPV tests, an effort led by Dr. Castle. Many data analyses are underway for the Guanacaste Project, for example, longitudinal analyses of HPV DNA, cytology, and visual appearance of the cervix among the 10,000 women during the 7 years of follow-up (Dr. Schiffman), and in-depth studies of HPV type variants and risk of viral persistence and progression focused particularly on HPV16 (Cooperative Agreement with Dr. Robert Burk at Albert Einstein College of Medicine). We are finding that multiple infections, though very common, show little evidence of synergy or antagonism with regard to either persistence or neoplastic progression. Clearance typically occurs within 6 months to 2 years after first infection. We observe that if infections become inapparent, they pose very low subsequent risk of precancer, even if they re-appear briefly due to yet undefined lapse in immune control. In other work, research continues on identifying and validating biomarkers of risk of progression. This includes the identification of novel tumor suppressor genes found to be methylated in cervical neoplasia. SUCCEED directed by Dr. Wang and now by Dr Wentzensen is focused on the identification of biomarkers of risk at each progressive disease stage, aimed to identify the molecular events that are necessary and sufficient for progression to cervical cancer. Frozen specimens, often multiple, from 2,500 women with varying grades of cervical neoplasia (including the ectocervix, transformation zone, and endocervix) have already been collected. In a new study at the same center in Oklahoma, Dr. Wentzensen is investigating the earliest discernible transitions from HPV infection to CIN3 and the best methods for colposcopic detection of CIN3. Dr. Castle launched an effort to validate HPV testing via self-sampling in the Mississippi Delta, a region with relatively high rates of cervical cancer. The project will investigate whether HPV screening might improve screening coverage and accuracy compared with conventional clinic-based cytology. Our newest cohort study also directed by Dr. Castle will be based on follow-up of 50,000 or more women found to be HPV DNA-positive during screening at Kaiser Permanente Northern California (KPNC). He has started a similar effort there on anal HPV and anal neoplasia at KPNC. Also, a cross-sectional study in Nigeria has been launched to investigate whether reported high prevalence of infection in older women is confirmed and, if so, to investigate why. Investigations on unusual age-specific HPV prevalence rates are very important for understanding HPV natural history and for designing rational screening programs. The study in Nigeria is also conducting a field evaluation of one low-cost HPV DNA test developing for resource-poor countries. A new effort to evaluate several low-cost molecular screening tests and strategies in 7,500 unscreened women living rural China will be launched in 2011. Finally, we are working on sharing the longitudinal data from NCI projects with collaborators for research and teaching, using a novel multi-media database system developed with engineers at the National Library of Medicine.